Abstract

Fructose consumption, which promotes insulin resistance, hypertension, and dyslipidemia, has increased by over 25% since the 1970s. In addition to metabolic dysregulation, fructose ingestion stimulates the hypothalamic-pituitary-adrenal (HPA) axis leading to elevations in glucocorticoids. Adolescents are the greatest consumers of fructose, and adolescence is a critical period for maturation of the HPA axis. Repeated consumption of high levels of fructose during adolescence has the potential to promote long-term dysregulation of the stress response. Therefore, we determined the extent to which consumption of a diet high in fructose affected behavior, serum corticosterone, and hypothalamic gene expression using a whole-transcriptomics approach. In addition, we examined the potential of a high-fructose diet to interact with exposure to chronic adolescent stress. Male Wistar rats fed the periadolescent high-fructose diet showed increased anxiety-like behavior in the elevated plus maze and depressive-like behavior in the forced swim test in adulthood, irrespective of stress history. Periadolescent fructose-fed rats also exhibited elevated basal corticosterone concentrations relative to their chow-fed peers. These behavioral and hormonal responses to the high-fructose diet did not occur in rats fed fructose during adulthood only. Finally, rats fed the high-fructose diet throughout development underwent marked hypothalamic transcript expression remodeling, with 966 genes (5.6%) significantly altered and a pronounced enrichment of significantly altered transcripts in several pathways relating to regulation of the HPA axis. Collectively, the data presented herein indicate that diet, specifically one high in fructose, has the potential to alter behavior, HPA axis function, and the hypothalamic transcriptome in male rats.

a. The percent of weight gained during the mid-adolescent stressor (PND37-49) was reduced in the stress cohorts (p<0.05) and fructose-fed animals gained more weight during this period (p<0.05). b. The fructose diet also significantly increased fasting glucose during mid-adolescence (p<0.05) irrespective of stress history. c. Glucose administration in the glucose tolerance test raised blood glucose in both chow and fructose stress & non-stress groups (p<0.05) as expected. However, fructose diet exacerbated this effect and fructose-fed rats had significantly higher blood glucose in the glucose challenge than the standard chow fed rats (p<0.05). d. Only a main effect of glucose administration (p < 0.05) was observed in analysis of plasma insulin; neither fructose nor stress, nor an interaction of either with the other or with glucose altered plasma insulin. Data shown are mean ± SEM; different letters indicate significant differences (p < 0.05) as assessed by post-hoc testing. NS=Non-stressed; S=Stressed; C=Saline-injected control; G=Glucose-injected

a. Periadolescent fructose-fed rats showed increased activity in the open field. b. Fructose-feeding during periadolescence reduced central tendency, while adolescent stress increased central tendency. c. Periadolescent fructose-fed rats reduced time spent in the open arms of the elevated plus maze. d, e, f. Periadolescent fructose-fed rats spent significantly less time struggling, had reduced latency to float, and spent more time immobile in the forced swim test than standard chow fed rats. g, h, i. Rats fed the high-fructose diet in adulthood only did not differ from chow controls in open field or elevated plus maze behavior. j, k, l. Rats that consumed the fructose diet in adulthood only did not change in either struggling (p>0.05) or immobility (p>0.05) in the forced swim. However, there was a numeric reduction in latency to float in the adult fructose-fed rats (t14=2.094 p=0.0549). Data shown are mean ± SEM; asterisk indicates a main effect of diet while letters indicate significant post-hoc effects with p < 0.05. NS=Non-stressed; S=Stressed

RT-PCR indicated upregulation of hypothalamic Crfr2 (c) and a non-significant 5-fold upregulation of Pomc (a) in periadolescent fructose-fed animals without an effect on Crfr1 (b). In animals fed fructose during adulthood only, there was a non-significant 5-fold upregulation of Pomc (d) but no effect was observed on either Crfr1 (e) or Crfr2 (f).